CN102603676A - Phosphodiesterase 4 inhibitor capable of avoiding vomiting reaction - Google Patents
Phosphodiesterase 4 inhibitor capable of avoiding vomiting reaction Download PDFInfo
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- CN102603676A CN102603676A CN2012100379803A CN201210037980A CN102603676A CN 102603676 A CN102603676 A CN 102603676A CN 2012100379803 A CN2012100379803 A CN 2012100379803A CN 201210037980 A CN201210037980 A CN 201210037980A CN 102603676 A CN102603676 A CN 102603676A
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- Prior art keywords
- phosphodiesterase
- inhibitors
- substituted
- reaction
- vomiting
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- 238000006243 chemical reaction Methods 0.000 title claims abstract description 28
- 206010047700 Vomiting Diseases 0.000 title claims abstract description 25
- 230000008673 vomiting Effects 0.000 title claims abstract description 24
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title claims abstract description 23
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 125000003118 aryl group Chemical group 0.000 claims abstract description 9
- 229940002612 prodrug Drugs 0.000 claims abstract description 7
- 239000000651 prodrug Substances 0.000 claims abstract description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 5
- -1 methoxyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 6
- 101000988419 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4D Proteins 0.000 abstract description 5
- 102100029170 cAMP-specific 3',5'-cyclic phosphodiesterase 4D Human genes 0.000 abstract description 5
- 208000024827 Alzheimer disease Diseases 0.000 abstract description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 abstract description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 abstract 1
- 235000010290 biphenyl Nutrition 0.000 abstract 1
- 239000004305 biphenyl Substances 0.000 abstract 1
- 230000001149 cognitive effect Effects 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 abstract 1
- 239000012453 solvate Substances 0.000 abstract 1
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 22
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 22
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 22
- 239000002512 suppressor factor Substances 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 7
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 7
- 229950005741 rolipram Drugs 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 230000003930 cognitive ability Effects 0.000 description 3
- 230000003920 cognitive function Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000024732 dysthymic disease Diseases 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 2
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 2
- 238000012347 Morris Water Maze Methods 0.000 description 2
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 2
- 229960002646 scopolamine Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000001519 thymoleptic effect Effects 0.000 description 2
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 1
- 208000003098 Ganglion Cysts Diseases 0.000 description 1
- 101001098805 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4A Proteins 0.000 description 1
- 101000988424 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4B Proteins 0.000 description 1
- 101000988423 Homo sapiens cAMP-specific 3',5'-cyclic phosphodiesterase 4C Proteins 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 101100296716 Mus musculus Pde4d gene Proteins 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 101150110109 PDE4D gene Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000005400 Synovial Cyst Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 102100037092 cAMP-specific 3',5'-cyclic phosphodiesterase 4A Human genes 0.000 description 1
- 102100029168 cAMP-specific 3',5'-cyclic phosphodiesterase 4B Human genes 0.000 description 1
- 102100029169 cAMP-specific 3',5'-cyclic phosphodiesterase 4C Human genes 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000006250 specific catalysis Methods 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D237/14—Oxygen atoms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
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- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a phosphodiesterase 4 inhibitor capable of avoiding a vomiting reaction. The phosphodiesterase 4 inhibitor is a compound or a pro-drug or a solvate represented by formula (I), wherein R1 is independent methoxyl, bromine and substituted aryl; X is a randomly substituted six-membered heterocycle; Y is -(CH2)n-, -NH(CH2)n- and -NH(CH2)n-O-, wherein n can be any one of 0, 1, 2 or 3; and Z is a randomly substituted aromatic ring or a randomly substituted heteroaromatic ring. The phosphodiesterase 4 inhibitor capable of avoiding the vomiting reaction is a novel biphenyl PDE4D inhibitor which is applicable to treating depression and Alzheimer's disease and improving cognitive competence, and is capable of avoiding a side effect such as the vomiting.
Description
Technical field
The present invention relates to a kind of technical field with the compound that suppresses phosphodiesterase; Especially a kind of biphenyl class PDE4D suppressor factor; A kind of specifically phosphodiesterase 4 inhibitors that can avoid vomiting reaction, this suppressor factor can be used for treating dysthymia disorders, alzheimer's disease and improve cognitive ability.
Background technology
Phosphodiesterase 4 (PDE4) mainly is distributed in inflammatory cell (mastocyte, scavenger cell, lymphocyte and epithelial cell) and the neurocyte.PDE4 and the central nervous system functions of immune system of unifying has confidential relation, and its suppressor factor is considered to act on the new antiphlogiston and the cns drug candidate of target spot in the cell.Because therefore the hydrolysis of the specific catalysis cAMP of PDE4 is exchanged the interior cAMP concentration of ganglion cell and is played a key role, and suppresses PDE4 and makes cAMP in the cell accumulated, produces various biological effects, comprises anti-inflammatory, antidepressant, hypermnesis and improves cognitive function etc.
First-generation PDE4 suppressor factor such as rolipram have good antidepressant effect, and causing its reason that can not go on the market is to suppress the side reactions such as nausea and vomiting that PDE4 brought.Compare with first-generation PDE4 suppressor factor, s-generation PDE4 suppressor factor has better result of treatment, but the PDE4 suppressor factor that does not also have so far can avoid vomitting goes on the market.Can reduce even avoid vomiting so press for one type of exploitation, but have antidepressant and improve the Novel PDE 4 inhibitors of cognitive function.
PDE4 can be divided into PDE4A, PDE4B, PDE4C, a PDE4D4 hypotype, and by separate A, B, C, a D4 genes encoding, each PDE4 gene all has a plurality of transcription units and promotor respectively, nearly 20 PDE4 isozymes.People such as Zhang Hanting discover that through what the PDE4D gene is pounded out mouse PDE4D and depression and cognitive function are closely related, and are also relevant with vomiting simultaneously, have document to confirm this supposition successively.
All experimental results show that the PDE4 suppressor factor might be a suppressor factor (Houslay, et al. 2005, DDT, 10,1503-2119) a kind of and the cAMP competition.This also just can explain reason that its curative ratio is low.
Summary of the invention
Technical problem to be solved by this invention is to above-mentioned prior art present situation, provide a kind of not with the non-competing type phosphodiesterase 4 inhibitors that can avoid vomiting reaction of cAMP competition.It is active that have this compound very high PDE4 and PDE4D hypotype suppress, and shows in the experimental result of animal, improving aspect the learning and memory, has than the better effect of thymoleptic first-generation PDE4 suppressor factor rolipram.In addition, in the vomiting experiment of beasle dog, do not observe yet and significantly cause the reaction of vomitting.Therefore, this compounds is expected to become the medicine that first can be avoided treatment dysthymia disorders, the alzheimer's disease of untoward reactions such as vomitting and improve cognitive ability.
The present invention solves the problems of the technologies described above the technical scheme that is adopted:
A kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction is characterized in that: (I) does by formula
Compound or the prodrug or the solvolyte of representative,
Wherein: R
1Be methoxyl group independently, bromine and substituted aryl;
X is any substituted hexa-member heterocycle;
Y is-(CH
2)
n-,-NH (CH
2)
n-,-NH (CH
2)
n-O-, wherein, the value of n can be any one digit number in 0,1,2,3;
Z is any substituted aromatic ring or any substituted hetero-aromatic ring.
2. a kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction according to claim 1 is characterized in that: described R
1Be
X-Y is
Z is any substituted aromatic ring.
3. a kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction according to claim 1, it is characterized in that: described X is
Compared with prior art, a kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction involved in the present invention, wherein, (I) does by formula
Compound or the prodrug or the solvolyte of representative,
R
1Be methoxyl group independently, bromine and substituted aryl;
X is any substituted hexa-member heterocycle;
Y is-(CH
2) n-,-NH (CH
2) n-,-NH (CH
2) n-O-, wherein, the value of n can be any one digit number in 0,1,2,3;
Z is any substituted aromatic ring or any substituted hetero-aromatic ring.
A kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction involved in the present invention be a kind of not with the non-competing PDE4D suppressor factor of cAMP competition; PDE4 and PDE4D hypotype had very high inhibition activity; Experimental result in animal shows; Improving aspect the learning and memory, have than the better effect of thymoleptic first-generation PDE4 suppressor factor rolipram.In addition, in the vomiting experiment of beasle dog, do not observe yet and significantly cause the reaction of vomitting.Therefore, this compounds is expected to become the medicine that first can be avoided treatment dysthymia disorders, the alzheimer's disease of untoward reactions such as vomitting and improve cognitive ability.
Embodiment
Below in conjunction with accompanying drawing embodiments of the invention are described in further detail.
A kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction, wherein, (I) does by formula
Compound or the prodrug or the solvolyte of representative,
R
1Be methoxyl group independently, bromine and substituted aryl;
X is any substituted hexa-member heterocycle;
Y is-(CH
2)
n-,-NH (CH
2)
n-,-NH (CH
2)
n-O-, wherein, the value of n can be any one digit number in 0,1,2,3;
Z is any substituted aromatic ring or any substituted hetero-aromatic ring.
Above-mentioned by formula (II) does
Compound or prodrug or the pharmacologically acceptable salt or the solvolyte of representative;
Wherein: Z is any substituted aromatic ring.
Above-mentioned by formula (III) does
Compound or prodrug or the pharmacologically acceptable salt or the solvolyte of representative;
Wherein: R
1Be independently methoxyl group and substituted aryl;
Y is-(CH
2)
n-,-NH (CH
2)
n-,-NH (CH
2)
n-O-, wherein, the value of n can be any one digit number in 0,1,2,3;
Z is any substituted aromatic ring or any substituted hetero-aromatic ring.
Formula (II) series compound is as follows:
| Compd. | Z |
| II-1 | 2-methoxyphenyl |
| II-2 | 2-chlorophenyl |
Formula (III) series compound is as follows:
| Compd. | R 1 | R 2 | R 3 | Y | Z |
| III-1 | 3-chlorophenyl | Cl | Cl | H | \ |
| III-2 | 3-chlorophenyl | H | H | -N(CH 2CH 2) 2-N- | 2-chlorophenyl |
| III-3 | 3-chlorophenyl | H | H | -NHCH 2CH 2O- | 2-methoxyphenyl |
| III-4 | Br | H | H | -NH CH 2CH 2O- | 2-methoxyphenyl |
| III-5 | MeO | H | H | -NH CH 2CH 2O- | 2-methoxyphenyl |
The compound of the present invention of formula (I) and formula (II) representative can be synthetic through the well-known method of describing in the chemical literature, sums up below to can be used for method of the present invention, as
Scheme 1Shown in.
Scheme?1
Get 3-replacement-4-methoxy toluene (2mmol) in 50ml two neck round-bottomed flasks after, add 0.356g (2mmol) N-bromo-succinimide (NBS) and the anhydrous tetracol phenixin of 20ml, be heated to backflow, thin-layer chromatography monitoring reaction process.After reaction is accomplished, filter, removal of solvent under reduced pressure promptly obtains 3-replacement-4-methoxyl group brooethyl benzene bullion, need not separate the reaction below the direct entering.
The 2mmol heterocyclic amine is added in the 25ml two neck round-bottomed flasks; After adding the 10ml dry DMF; Add 0.417g Anhydrous potassium carbonate (3mmol) again, stirring at normal temperature 1h added the brooethyl 3-replacement-4-methoxyl group brooethyl benzene bullion that a last step obtains; Stirring at normal temperature reaction 12h, thin-layer chromatography monitoring reaction process.After reaction is accomplished, filter, after DMF is removed in decompression, get bullion.Carry out column chromatography for separation and obtain target compound.
Target bonded spectral data:
Compound?II-1?(ZX-I01)：Yield:?65%；ESI–MS:?m/z?424.0?([M+H]
+),?446.0?([M+Na]
+)；
1H?NMR?(400MHz,?CDCl
3):?2.65?~?2.70?(m,?4H),?3.05?~?3.15?(m,?4H),?3.81?(s,?3H,?MeO),?3.85?(s,?3H,?MeO),?3.89?(s,?2H,?CH2),?6.84?~?7.01?(m,?5H),?7.27?~?7.36?(m,?4H),?7.41(s,?1H),?7.53(s,?1H)；
Compound?II-2?(ZX-I02)：Yield:?63%；ESI–MS:?m/z?427.5(M
+),?428.5([M+1]
+),?429.5?([M+2]
+)；
1H?NMR?(400MHz,?CDCl
3):?2.63?~?2.70?(m?,4H),?3.09?~?3.12?(m,?4H),?3.82?(s,?3H,?MeO),?3.89?(s,?2H,?CH
2),?6.94?~?6.98?(m,?2H),?7.03?(d,?
J?=?8.0Hz,?1H),7.21?(t,?
J?=?7.6Hz,?1H),7.28?~?7.40?(m,?5H),7.43?(s,?1H),7.55?(s,?1H)；
Compound?III-1?(ZX-I03)：Yield:?43%；ESI–MS:?m/z?395.6(M
+),?396.5?([M+1]
+),?397.5?([M+2]
+)；
1H?NMR(400MHz,?CDCl3):?3.80?(s,?3H,?MeO),?5.29?(s,?2H,?CH
2),?6.92?(d,?
J?=?7.6Hz,?1H),?7.29?~?7.39?(m,?3H),?7.45?~?7.48?(m,?2H)?,7.64?(d,?
J?=?2.0Hz,?1H),?7.77?~?7.8?(m,?2H)；
Compound?III-2?(ZX-I06)：Yield:?33%；ESI–MS:?m/z521.5(M
+),?522.5([M+1]
+),?523.5?([M+2]
+)；
1H?NMR?(400MHz,?CDCl
3):?3.20?~?3.30(m,?4H),?3.50?~?3.60(m,?4H),?3.82?(s,?3H,?MeO),?5.14?(s,?2H,?CH
2),?6.86?~?7.00?(m,?2H),?7.08?(t,?
J?=?8.0Hz,?1H),?7.15?(d,?
J?=?9.6Hz,?1H),?7.28?~?7.34?(m,?4H),?7.39?~?7.44?(m,?3H),?7.46?(d,?
J?=?8.4Hz,?1H),?7.51(s,?1H),?7.68?(d,?
J?=?1.6Hz,?1H)；
Compound?III-3?(ZX-I07):?Yield:?45%；ESI–MS:?m/z?492.6(M
+),?493.6([M+1]
+),?494.6?([M+2]
+),?514.6([M+Na]
+),?530.6([M+K]
+)；
1H?NMR?(400MHz,?CDCl
3):?3.64(t,?
J?=?4.8Hz,?2H),?3.79(s,?3H,?MeO),?3.84(s,?3H,?MeO),?4.13((t,
J?=?4.8Hz,?2H),?5.16?(s,?2H,?CH
2),?6.78(d,?
J?=?9.6Hz,?1H),?6.85?~?6.98?(m,?6H),?7.28?~?7.44(m,?4H),?7.505(s,?1H),?8.02(s,?1H)；
Compound?III-4?(ZX-I11):?Yield:?42%；ESI–MS:?m/z?482.4?([(M-1)+Na]
+),?484.4?([(M+1)+Na]
+)；
1H?NMR(400MHz,?CDCl
3):?3.64(t,?
J?=?4.8Hz,?2H),?3.85(s,?3H,?MeO),?3.96(s,?3H,?MeO),?4.18((t,?
J?=?4.8Hz,?2H),?5.08?(s,?2H,?CH
2),6.73?~?6.99(m,?5H),?7.36(d,?
J?=?7.2Hz,?1H),?7.53?~?7.55(m,?1H),?7.65(d,?
J?=?1.2Hz,?1H),7.72?~?7.74(m,?1H)；
Compound?III-5?(ZX-I12):?Yield:?28%；ESI–MS:?m/z?412.7([M+1]
+),?434.7([M+Na]
+),?450.7([M+K]
+);?
1H?NMR?(400MHz,?CDCl3):?3.79(s,?3H,?MeO),?3.81(s,?3H,?MeO),?3.85?~?3.87(m,?5H,?MeO,?CH
2),?4.19(t,?
J?=?5.2Hz,?2H),?4.68(s,?2H,?CH
2),?6.76?~?6.94(m,?7H),?7.00?(d,?
J?=?10Hz,?1H),?7.34(d,?
J?=?10Hz,?1H);
Phosphodiesterase 4 suppresses activity experiment
1, experimental technique
What the active mensuration that suppresses PDE4 adopted is the IMAP technology, and this method can accurate and stable record the inhibition activity of compound to PDE4.
2, experimental result
Table 1 Novel PDE 4 inhibitors II-1, II-2, III-1～III-3 is active to the inhibition of PDE4, PDE4D4 and PDE4D5
Table 2 Novel PDE 4 inhibitors ZX-111 and ZX-112 are active to the inhibition of PDE4
Experimentation on animals
1. Novel PDE 4 inhibitors III-3 is to the influence of the acquired obstacle learning and memory of little mouse of learning and memory due to the Scopolamine
1.1 method
60 kunming mices are divided into 6 groups at random; Every group 10, i.e. blank control group, model group, rolipram control group, the basic, normal, high dose groups of III-3,1 week of successive administration the back adopt the Morris water maze to carry out the study of behaviour test; Tested preceding 20 minutes; Except that blank intraperitoneal injection of saline, all the other each groups are all injected the Scopolamine injection liquid, train continuously 4 days; Carried out the space exploration experiment on the 5th day, record is respectively organized mouse and is passed through the target area time for the first time, passes through the target area number of times and the target quadrant residence time.
Table 3 Novel PDE 4 inhibitors III-3 is to the influence (
± S) of learning memory disorder property mouse Morris water maze test
Annotate: compare with model group, * P 0.05, * * P < 0.01
2. Novel PDE 4 inhibitors III-3 causes the preliminary study of vomiting reaction
2.1 method
6 beasle dogs are divided into 2 groups at random, promptly rolipram 0.5 mg/kg control group (0.5 mg/ml, 1ml/kg) and solvent control group (5% DMSO, 1ml/kg), to irritate the mode administration of stomach.The continuous observation 120 minutes, the observation animal has or not vomiting reaction, and observation index is that nauseating retch, a large amount of hydrostomia and vomiting appear in animal, writes down latent period.After one week; 6 beasle dogs are divided into 2 groups again at random, i.e. rolipram control group and III-3 administration group, (liquor strength is 0.5 mg/ml to give high dosage rolipram 0.5 mg/kg with the mode of irritating stomach; Administration volume 1 ml/kg), observed continuously in the same way 120 minutes.
1.2 experimental result
Table 4 gives the vomiting reaction situation of dog behind the Novel PDE 4 inhibitors III-3
Most preferred embodiment of the present invention is illustrated, and various variations or the remodeling made by those of ordinary skills can not depart from the scope of the present invention.
Claims (3)
1. the phosphodiesterase 4 inhibitors that can avoid vomiting reaction, it is characterized in that: (I) does by formula
Compound or the prodrug or the solvolyte of representative,
Wherein: R
1Be methoxyl group independently, bromine and substituted aryl;
X is any substituted hexa-member heterocycle;
Y is-(CH
2)
n-,-NH (CH
2)
n-,-NH (CH
2)
n-O-, wherein, the value of n can be any one digit number in 0,1,2,3;
Z is any substituted aromatic ring or any substituted hetero-aromatic ring.
2. a kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction according to claim 1 is characterized in that: described R
1Be
X-Y is
;
Z is any substituted aromatic ring.
3. a kind of phosphodiesterase 4 inhibitors that can avoid vomiting reaction according to claim 1 is characterized in that: described X is
.
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|---|---|---|---|
| CN201210037980.3A CN102603676B (en) | 2012-02-20 | 2012-02-20 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting reaction |
| EP12869037.7A EP2784068B1 (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting |
| PCT/CN2012/080593 WO2013123766A1 (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting |
| PT128690377T PT2784068E (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting |
| ES12869037.7T ES2556552T3 (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of preventing vomiting |
| US14/373,347 US9051273B2 (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of avoiding vomiting |
| JP2014550614A JP5851631B2 (en) | 2012-02-20 | 2012-08-25 | Phosphodiesterase 4 inhibitor capable of preventing vomiting reaction |
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| CN1498211A (en) * | 2001-01-22 | 2004-05-19 | ����˹��ҩ�﹫˾ | Aniline derivative using as phosphodiesterase 4 inhibitor |
| US20110065691A1 (en) * | 2006-02-28 | 2011-03-17 | Kaplan Alan P | Therapeutic piperazines |
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| US6479495B1 (en) * | 1997-09-29 | 2002-11-12 | Aventis Pharmaceuticals Inc. | Aminoalkylphenol derivatives and related compounds |
| CN1142148C (en) * | 1997-11-19 | 2004-03-17 | 兴和株式会社 | Pyridazine derivatives and drugs containing the same as the active ingredient |
| JP2000281660A (en) * | 1999-03-29 | 2000-10-10 | Sumitomo Pharmaceut Co Ltd | Quinazoline derivative |
| TW200804347A (en) * | 2006-01-10 | 2008-01-16 | Janssen Pharmaceutica Nv | Urotensin II receptor antagonists |
| CA2722582A1 (en) * | 2007-11-21 | 2009-05-28 | Decode Genetics Ehf. | Biaryl pde4 inhibitors for treating inflammation |
| US9457030B2 (en) * | 2012-10-29 | 2016-10-04 | Board Of Regents Of The University Of Nebraska | Compositions and methods for the treatment of juvenile neuronal ceroid lipofuscinosis and related disorders |
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| CN1498211A (en) * | 2001-01-22 | 2004-05-19 | ����˹��ҩ�﹫˾ | Aniline derivative using as phosphodiesterase 4 inhibitor |
| US20110065691A1 (en) * | 2006-02-28 | 2011-03-17 | Kaplan Alan P | Therapeutic piperazines |
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| SHILONG ZHENG ET AL: "Design, Synthesis, and Structure-Activity Relationship, Molecular Modeling, and NMR Studies of a Series of Phenyl Alkyl Ketones as Highly Potent and Selective Phosphodiesterase-4 Inhibitors", 《J. MED. CHEM.》, vol. 51, 2 December 2008 (2008-12-02), pages 7673 - 7688 * |
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| CN106632070A (en) * | 2016-12-16 | 2017-05-10 | 徐江平 | Preparation method for chlorbipram PDE4-inhibitor |
| CN106632070B (en) * | 2016-12-16 | 2019-08-06 | 广州兰晟健智医药科技有限公司 | A kind of preparation method of PDE4 inhibitor chlorine than Pulan |
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| ES2556552T3 (en) | 2016-01-18 |
| PT2784068E (en) | 2016-02-08 |
| EP2784068B1 (en) | 2015-10-21 |
| CN102603676B (en) | 2014-02-12 |
| US9051273B2 (en) | 2015-06-09 |
| WO2013123766A1 (en) | 2013-08-29 |
| EP2784068A4 (en) | 2014-10-22 |
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